Conjugating a biologically active polypeptide to a water-soluble polymer avoids some of the drawbacks of injectable delivery. In particular, water-soluble polymer-biologically active polypeptide conjugates can allow for conjugates having reduced immunogenicity and antigenicity, increased water solubility, greatly increased half-lives compared to their unconjugated counterparts (as a result of decreased clearance through the kidney and/or decreased enzymatic degradation in the systemic circulation), and less frequent dosing requirements (as a result of having a greater half-life). Harris et al. have provided a review of the effects of conjugating a water-soluble polymer to an active agent. Harris et al. (2003) Nat. Rev. Drug Discov. 2(3):214-221.
A polyethylene glycol derivative can serve as the water-soluble polymer used to form conjugates with biologically active polypeptides. When an active agent is conjugated to a polymer of polyethylene glycol or “PEG,” the conjugated active agent is conventionally referred to as being “PEGylated.”
The commercial success of PEGylated active agents such as PEGASYS® PEGylated interferon alpha-2a (Hoffmann-La Roche, Nutley, N.J.), PEG-INTRON® PEGylated interferon alpha-2b (Schering Corp., Kennilworth, N.J.), MACUGEN® pegaptanib sodium injection (Pfizer Inc., New York, N.Y.), SOMAVERT® pegvisomant (Pfizer Inc., New York, N.Y.) and NEULASTA® PEG-filgrastim (Amgen Inc., Thousand Oaks, Calif.) demonstrates that administration of a conjugated form of an active agent can have significant advantages over the unconjugated counterpart.
“Reversible PEGylation”—the approach where the active agent (or a moiety having increased activity compared to the PEGylated active agent) is released in vivo—has been proposed in those instances where PEGylaton results in a conjugate that has relatively low pharmacologic activity. For example, U.S. Patent Application Publication No. 2005/0079155 describes conjugates using reversible linkages. As described in this publication, reversible linkages can be effected through the use of an enzyme substrate moiety. It has been pointed out, however, that approaches relying on enzymatic activity are dependent on the availability of enzymes. See Peleg-Schulman (2004) J. Med. Chem. 47:4897-4904. Thus, additional approaches that do not rely on enzymatic processes for degradation have been described as being desirable.
One such approach for reversible PEGylation describes a polymeric reagent comprising a fluorene moiety upon which a branched polymer is attached using maleimide chemistry. See Peleg-Schulman (2004) J. Med. Chem. 47:4897-4904 and WO 2004/089280. U.S. Patent Application Publication No. 2006/0293499, describes (among other things) conjugates having a degradable linkage and polymeric reagents useful in preparing such conjugates. Each polymeric reagent has a particular strategy (typically carried out through a particular functional group or groups) to provide the abilities to first initially attach the water-soluble polymer to the active agent and then subsequently release the active agent (or some pharmacologically active residue of the conjugate) in vivo.
Notwithstanding these described polymeric reagents, however, there continues a need to provide additional polymeric reagents, with (for example) different or alternative strategies for initial coupling to an active agent and subsequent release of a pharmacologically active residue in vivo. Thus, the present invention seeks to solve these and other needs in the art.